Cholestyramine and Colestipol

Currently available BAS include cholestyramine, colestipol and colesevelam hydrochloride (colestimide). Cholestyramine comprises a long-chain polymer of styrene with divinylbenzene trimethylbenzylammonium groups, whereas colestipol is a long-chain polymer of l-chloro-2,3-epoxypropane with diethylenetriamine. Colesevelam HCl is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and 6-bromo-hexyl-trimethylammonium bromide. Bile-acid binding is enhanced and stabilised in the latter compound by long hydrophobic sidechains, increased density of primary amines, and quaternary amine sidechains. For this reason, colesevelam HCl exhibits increased affinity, specificity and capacity to bind bile acids compared with the other BAS. Colesevelam HCl also binds dihydroxy and trihydroxy bile acids with equal affinity, contrasting with cholestyramine and colestipol that preferentially bind dihydroxy bile acids (CDCA and deoxycholic acid). The latter BAS can lead to an imbalance towards trihydroxy bile acids and a more hydrophilic bile-acid pool. 

Cholestyramine and colestipol resins may delay or reduce the absorption of concomitant oral medication by binding the drugs in the gut. Take other drugs at... 

The principal precaution with use of the bile acid resins is the possibility of impaired absorption of other drugs given orally at the same time. Cholestyramine and colestipol can bind many other drugs, such as digitoxin, phenobarbital, chlorothiazide, and warfarin, and delay or prevent their absorption. For this reason, other drugs should always be taken at least 1 hour before or 4 to 6 hours after the resin. The resins can also decease absorption of fat-soluble vitamins. 

Prior to 1987, the lipid-lowering armamentarium was limited essentially to dietary changes (reductions in saturated fats and cholesterol), the bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), the fibrates, and probucol. Unfortunately, all of these treatments have limited efficacy or tolerability or both. Substantial reductions in LDL cholesterol (up to 47%) accompanied by increases in HDL cholesterol of up to 32% could be achieved by the combination of a lipid-lowering diet, a bile acid sequestrant, and the subsequent addition of nicotinic acid (Illingworth et al., 1981). However, this therapy is not easy to administer or tolerate and was therefore often unsuc-... 

Bile acid sequestrates are anion-exchange resins, which sequester bile acid in the intestine. Cholestyramine and colestipol are the most commonly used in this category, which by this mechanism prevents bile acid re-absorption and causes decreased absorption of exogenous cholesterol and increased metabolism of endogenous cholesterol into bile acid in the liver by preventing enterohepatic recirculation. This leads to an increased expression of LDL receptors in liver and causes increased removal of LDL from blood and reduces the LDL cholesterol in the plasma. 

C. Bile acid binding resins cholestyramine and colestipol... 

Pharmacokinetics Cholestyramine and colestipol are taken orally. Because they are insoluble in water and are very large (molecular weights are greater than 106), they are neither absorbed nor metabolically altered by the intestine. Instead, they are totally excreted in the feces. 

Other oral adsorbents have specific uses. Fuller s earth and bentonite (both natural forms of aluminium silicate) bind and inactivate the herbicides, paraquat (activated charcoal is superior) and diquat cholestyramine and colestipol will adsorb warfarin. 

Cholestyramine and Colestipol. Other interactions involving complexation might be anticipated when cholestyramine (e.g., Questran) and colestipol (Coles-tid) are used. These resinous materials, which are not absorbed from the GI tract, bind with bile acids and prevent their reabsorption. In addition, cholestyramine and colestipol can bind with drugs (e.g., digoxin and warfarin) that are present in the GI tract. To minimize the possibility of an interaction, the interval between the administration of cholestyramine or colestipol and another drug should be as long as possible. 

Drug Interactions Various drugs can decrease T absorption. Drugs such as aluminum hydroxide, ferrous sulfate, sucralfate, and calcium carbonate should be separated from T administration by 1 to 2 hours. Bile acid sequestrants (cholestyramine and colestipol) must be separated from T by at least 4 hours and preferably 6 hours. CYP450 enzyme inducing drugs such as phenytoin, carba-mazepine, rifampin, and phenobarbital can increase T requirements. 

The polymeric ion-exchange resins cholestyramine and colestipol act by binding bile acids, preventing their reabsorption so promoting hepatic conversion of cholesterol into bile acids. This results in increased LDL-receptor activity of liver cells, which increases the break down of LDL-cholesterol. In this way the compounds effectively reduce LDL-cholesterol (but can aggravate hypertriglyceridaemia). 

A wide variety of pharmacological agents for cholesterol lowering in adults are available, including (1) bile acid-binding resins (cholestyramine and colestipol), (2) niacin. 

Structures of bile acid sequestrants. Cholestyramine and colestipol are hydrophilic yet water-insoluble, nondigestible, and nonabsorbable synthetic resins. They bind bile acids in the intestine to increase their loss in feces and thereby decrease plasma cholesterol levels. 

Cholestyramine and colestipol are resins that complex bile salts, preventing their reabsorption from the GI tract —>4 feedback inhibition of 7 alpha hydroxylase —>T synthesis of new bile salts —liver cholesterol — T LDL receptors —plasma LDL. 

Cholestyramine and colestipol are bile acid sequestranls that enhance cholesterol loss into the feces, thereby stimulating new bile salt synthesis, which lowers liver cholesterol levels and consequently plasma LDL levels. Their adverse effects are also listed. 

Answer D. Cholestyramine and colestipol are resins that sequester bile acids in the gut, preventing their reabsorption. This leads to release of their feedback inhibition of 7-alpha hydroxylase and the diversion of cholesterol toward new synthesis of bile acids. Increase in high-affinity LDL receptors on hepatocyte membranes decreases plasma LDL. These drugs have a small but significant effect to increase plasma HDL rather than decrease it, but their ability to increase TGs precludes their clinical use in the management of hypertriglyceridemias. 

Cholesterol-Reducing Agents. Hypercholesterolemia is well known as a major risk factor for coronary heart disease. In clinical practice, two main hypocholestrolemic agents are commonly used. One is the 3-hy-droxy-3-methylgrutaryl coenzyme A (HMG-CoA) reductase inhibitors (such as Lipitor) another is the bile acid sequestrants, such as cholestyramine and colestipol (97), which bind bile acid in the intestinal lumen and thus increase their excretion. The main drawback of... 

Ans D Cholestyramine and colestipol are resins that sequester bile acids in... 

Hepatic enzyme inducers (for example, phenytoin) may increase hepatic degradation of levothyroxine, causing increased dosage requirements of levothyroxine. Concomitant use with somatrem may accelerate epiphyseal maturation. Intravenous phenytoin may release free thyroid from thyroglobulin. Cholestyramine and colestipol may decrease absorption. 

Aluminum salts, cholestyramine, and colestipol may decrease absorption of /3 blockers. Pheny-toin, rifampin, and phenobarbital, as well as smoking, induce hepatic biotransformation enzymes and may decrease plasma concentrations of /3 receptor antagonists that are metabolized extensively (e.g., propranolol). Cimetidine and hydralazine may increase bioavailability of propranolol and metoprolol by affecting hepatic blood flow, fi Receptor antagonists can impair the clearance o/lidocaine. 

The two established bUe-acid sequestrants or resins (cholestyramine and colestipol) are most often used as second agents if statin therapy does not lower LDL-C levels sufficiently. When used with a statin, cholestyramine and colestipol usually are prescribed at submaximal doses. Maximal doses can reduce LDL-C by up to 25% but are associated with unacceptable gastrointestinal (GI) side effects (bloating and constipation) that limit compliance. Colesevelam is a newer bile-acid sequestrant that is prepared as an anhydrous gel and taken as a tablet. It lowers LDL-C by 18% at its maximum dose. The safety and efficacy of colesevelam have not been studied in children or pregnant women. 

The resins are generally safe, as they are not systemically absorbed. Since they are administered as chloride salts, rare instances of hyperchloremic acidosis have occurred. Since they increase triglyceride levels, severe hypertriglyceridemia is a contraindication to the use of cholestyramine and colestipol. At present, there are insufficient data on the effect of colesevelam on triglyceride levels. 

Cholestyramine and colestipol both are available as a powder that must be mixed with water and drunk as a slurry. The gritty sensation is unpleasant to patients initially but can be tolerated. Colestipol is available in a tablet that reduces the complaint of grittiness but not the GI symptoms. Colesevelam is available as a hard capsule that absorbs water and creates a soft, gelatinous material that allegedly minimizes the potential for GI irritation. 

Patients taking cholestyramine and colestipol complain of bloating and dyspepsia, which can be substantially reduced if the drug is completely suspended in liquid several hours before ingestion. Constipation may occur but sometimes can be prevented by adequate daily water intake and psyllium, if necessary. Colesevelam may be less likely to cause the dyspepsia, bloating, and constipation observed in patients treated with cholestyramine or colestipol. 

G1 distress, nausea, and vomiting can be minimized by administration of tetracyclines with food. Cholestyramine and colestipol can bind orally administered tetracychnes and interfere with their absorption. Generally, tetracyclines should be administered 2 hours before or 2 hours after meals and other drugs that interfere with their absorption. 

A. Mechanism and Effects Bile acid-binding resins (cholestyramine and colestipol) are large nonabsorbable polymers that bind bile acids and similar steroids in the intestine. 

Bile acid sequestrants are indicated for the treatment of hypercholesterolemia in patients who do not adequately respond to dietary modifications. They may be used either alone or in combination with HMGRIs or niacin. These combinations often can achieve a 50% reduction in plasma LDL levels. Cholestyramine, but neither colestipol nor colesevelam, also is approved for the relief of pruritus associated with partial biliary obstruction. Bile acid sequestrants should not be used to treat hypertriglyceridemias or mixed hyperlipoproteinemias in which hypertriglyceridemia is the primary concern. These compounds also are contraindicated in patients with cholelithiasis or complete biliary obstruction because of the impaired secretion of bile acids caused by these conditions. Finally, cholestyramine and colestipol are contraindicated in patients with primary biliary cirrhosis, because this can further raise serum cholesterol (7,15,21). 

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